{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:47:00Z","timestamp":1769849220637,"version":"3.49.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL130856, HL135853, HL14868"],"award-info":[{"award-number":["HL130856, HL135853, HL14868"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["2T32EB014836-06A"],"award-info":[{"award-number":["2T32EB014836-06A"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Hemophilia A (HA) is the most common X-linked bleeding disorder, occurring in 1 in 5,000 live male births and affecting &amp;gt;1 million individuals worldwide. Although advances in protein-based HA therapeutics have improved health outcomes, current standard-of-care requires infusion 2-3 times per week for life, and 30% of patients develop inhibitors, significantly increasing morbidity and mortality. There are thus unmet medical needs requiring novel approaches to treat HA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We tested, in a highly translational large animal (sheep) model, whether the unique immunological and biological properties of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) could enable them to serve as cellular delivery vehicles to provide long-term expression of FVIII, avoiding the need for frequent infusions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that autologous BM-MSCs can be isolated, transduced with a lentivector to produce high levels of ovine (o)FVIII, extensively expanded, and transplanted into adult animals safely. The transplanted cells engraft in multiple organs, and they stably produce and secrete sufficient quantities of FVIII to yield elevated plasma FVIII levels for at least 15 weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These studies thus highlight the promise of cellular-based gene delivery approaches for treating HA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1070476","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T10:09:36Z","timestamp":1669975776000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels"],"prefix":"10.3389","volume":"13","author":[{"given":"Brady","family":"Trevisan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailey","family":"Medder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Lankford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Combs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Owen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Atala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher D.","family":"Porada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gra\u00e7a","family":"Almeida-Porada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1002\/jcp.20959","article-title":"From the laboratory bench to the patient\u2019s bedside: An update on clinical trials with mesenchymal stem cells","volume":"211","author":"Giordano","year":"2007","journal-title":"J Cell Physiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.839844","article-title":"Mesenchymal stromal cells for enhancing hematopoietic engraftment and treatment of graft-Versus-Host disease, hemorrhages and acute respiratory distress syndrome","volume":"13","author":"Ringden","year":"2022","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.01.005","article-title":"Therapeutic mesenchymal stromal cells for immunotherapy and for gene and drug delivery","volume":"16","author":"Almeida-Porada","year":"2020","journal-title":"Mol Ther Methods Clin Dev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.10.3838","article-title":"Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli","volume":"99","author":"Di Nicola","year":"2002","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13287-017-0503-8","article-title":"Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model","volume":"8","author":"Joswig","year":"2017","journal-title":"Stem Cell Res Ther"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087238","article-title":"Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo","volume":"9","author":"Isakova","year":"2014","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2013.06.002","article-title":"Hemophilia a in the third millennium","volume":"27","author":"Franchini","year":"2013","journal-title":"Blood Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.03.001","article-title":"Defining the optimal FVIII transgene for placental cell-based gene therapy to treat hemophilia a","volume":"17","author":"El-Akabawy","year":"2020","journal-title":"Mol Ther - 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